Fat: an emerging player in the field of atrial fibrillation

This editorial refers to ‘Atrial fibrillation is associated with the fibrotic remodelling of adipose tissue in the subepicardium of human and sheep atria’†, by P. Haemers et al., on page 53. Trigger and substrate are considered the cornerstones for initiation and persistance of atrial fibrillation (AF).1 Beyond changes in atrial size, fibrosis, oxidative stress, inflammation, and tissue infiltration have been added to the list of factors associated with structural remodelling.2 Changes in tissue architecture lead to functional disorganization, influence electrophysiological conditions, and finally result in a higher risk of AF. Epicardial adipose tissue has an important endocrine and inflammatory activity, and, given its location with direct apposition to coronary arteries and myocardial tissue, pericardial fat may play a central role in the pathogenesis of cardiovascular disease.3–5 Previous data suggest that pericardial fat volume is highly associated with paroxysmal and persistent AF independent of traditional risk factors including body mass index and left atrial enlargement, and is also predictive of recurrence of AF after AF ablation.6–8 Location of adipose tissue and types of fat deposits around the heart. This study by Haemers and colleagues12 investigated the pathophysiological significance of adipose tissue infiltrates, which are commonly observed in the atrial myocardium. The relationship between the histological characteristics of fatty infiltrations of atrial myocardium and the clinical history of individual patients was retrospectively assessed in human right atrial specimens collected during cardiac surgery. Left atrial samples were collected in a limited number of patients, in which a left atrial incision was necessary during the procedure mainly for mitral valve surgery. Additionally, atrial adipose tissue characteristics and their association with the progressive nature of AF were prospectively investigated in a sheep model of persistent AF. Based on their findings, the authors conclude that fatty infiltrates may contribute to the progressive fibrosis of subepicardial areas of the atrial myocardium which may result in changes in tissue architecture, conduction disorders. and electrical heterogeneity. Interestingly, there was no relationship between the extent of fatty infiltrations and the persistence of AF. However, there are some methodological limitations in the assessment of the extent of fatty infiltrations on histology that could have masked small changes. Such limitations include sampling of a limited area of the atrium that may cause variations in the extent of adipose tissue within a sample and expression of the extent of adipose tissue against total myocardial area that may by influenced by structural changes including hypertrophy. Fibrotic remodelling may partially explain the lack of an increase in fatty infiltrations, since only adipocytes were taken into account to assess the extent of adipose tissue infiltrations. Additionally, in the AF sheep model, magnetic resonance imaging revealed a higher absolute volume of total atrial adipose tissue, but accuracy of assessment of smaller fatty infiltrations was limited by resolution. However, more fatty infiltrations could be observed by histological assessment in the AF sheep model. Subepicardial adipose infiltration could be a physiological component of the atrial myocardial histology that may accumulate and become inflammatory and fibrotic under some clinical conditions including obesity and ageing. Thus, the lack of a relationship between the extent of fatty infiltrations and the persistence of AF in the present study is intruiging but may indicate the complexity of the underlying mechanisms. Left atrial structure is the major player involved in the development of AF. However, in the study under discussion,12 findings were mainly based on human right atrial specimens collected during cannulation for the extracorporeal circulation performed for routine cardiac surgery. Left atrial samples were collected only in a limited number of patients, but showed similar fibro-fatty infiltrates. In the AF sheep model, a detailed histological analysis of both right and left atria revealed a higher rate of fatty infiltrations in the right as compared with the left atrium. However, the process of fibrotic remodelling of the subepicardial area including fibrosis of the adipose tissue infiltrates, inflammatory infiltrates, and thick epicardium was similar between both atria. Inflammation-induced fibrosis of infiltrating subepicardial adipose tissue has been proposed as a novel concept of substrate progression in AF.12 However, whether these pure fibrotic infiltrations are the end-stage of fibrotic remodelled fatty infiltrations remains speculative. Data showing the progressive transformation of fatty infiltrates in fibrosis in the same individuals over time are lacking. Thus, this study provides no direct evidence for a transition from fatty to fibrotic infiltrates in patients. The major finding of the study is that the more fibrosis there is, the less adipose tissue is present in the atrial subepicardium. However, there is some evidence suggesting the possibility that such a transition process could be involved in AF progression, including the inverse correlation between the extent of subepicardial adipose tissue and the severity of remodelled epicardium indicated by the amount of fibrosis in both human and sheep atria. Additionally, in atrial sections, there is an apparent change from little, to moderate, and to marked fibrosis of the adipose tissue. Finally, the presence of necrotic adipocytes at the contact zone of immune aggregates indicates that a cell removal process may contribute to the replacement of adipose tissue by fibrosis. Left atrial dilatation, conduction abnormalities, and increased vulnerability to AF have been shown in obese sheep maintained on a high-calorie diet.2 Thus, obesity is associated with structural changes of the atria including left atrial enlargement, increased profibrotic transforming growth facator-β1 (TGF-β1) expression, interstitial atrial fibrosis, and conduction disorders resulting in an increased propensity for AF. Additionally, obesity is associated with infiltration of contiguous posterior left atrial myocardium by epicardial fat in close proximity to the pulmonary veins, representing a unique substrate for AF.2 Subepicardial adipose tissue has endocrine properties and produces adipokines, chemokines, inflammatory cytokines, and growth factors, including activin A, that can freely diffuse into the adjacent myocardium and may result in fibrotic changes on the atrial myocardium.13,14 The study by Haemers and colleagues adds an important piece of evidence supporting a novel concept of substrate progression in AF by inflammation-induced fibrosis of subepicardial adipose tissue infiltration.12 However, additional mechanisms beyond obesity including rapid atrial pacing and AF itself have been shown to be involved in the regulation of adipose tissue accumulation.6,15 Inflammation-induced fibrosis of infiltrating subepicardial adipose tissue—a novel concept of substrate progression in atrial fibrillation? Conflict of interest: none declared.